The Current Tragedy of Compounding Pharmacies is Not a Surprise

Scott Sutton, Ph.D.
The Microbiology Network, Inc.

The current fungal meningitis crisis is a tragedy, but one that could have been avoided if clear warning signs had been heeded. To understand the risks we have been running, we need to understand clearly the differences in controls and intents between GMP pharmaceutical manufacture of sterile products and a pharmacy compounding “sterile” products.   These differences are reflected in the regulation of pharmaceutical manufacturing by 21 CFR 211 (GMP) vs the regulation of compounding pharmacies by individual states relying on USP <797> “Pharmaceutical Compounding – Sterile Preparations” as the source document.    The fundamentally different approaches to preparation of sterile product taken reflects the different purposes – the GMP is designed to ensure a reproducible, stable drug product suitable for interstate commerce and storage, the pharmacist’s preparation is meant for for immediate use, made in small amounts for a specific patient in response to a doctor’s script.  This basic difference in intent has led, predictably, to this situation as externally sourced “compounding pharmacies” have begun to manufacture in batch sizes up in the thousands of units for national distribution.

According to a recent ISMP Medication Safety Alert, the 2008 revision of the US Pharmacopeia (USP) Chapter <797> left many facilities unable to meet the published standards for sterile compounding.  It is true that this revision tightened up the expectations for the relaxed pharmacy practices associated with sterile compounding prior to this point.  That this minimal level of expected cleanroom maintenance and process control should render pharmacies flummoxed is worrisome as a separate consideration.  However, the ISMP alert goes on to state that the resultant escalation in drug shortages (presumably because pharmacies were no longer compounding sub-par medications) led to a steady increase in external sterile compounding pharmacy services. According to this article, 66% of all hospital pharmacies that participated in a 2011 survey outsource some portion of their sterile compounding.   In other words, it is implied that the minimal requirements for patient safety in USP <797> from 2008 led directly to this crisis.

It is important to remember that the revision to USP <797> was in fact sparked by the obvious problems in sterile pharmacy compounding practices.  Now, it is the assumption that a pharmacy is compounding for an individual patient with a specific doctor’s script to guide the compounding.  The use of the medication will be relatively rapid, not allowing time for low levels of bacterial contamination to proliferate in the “sterile” compound.   This understanding is implicit in the recognition of three different levels of “sterile” medications, rated according to risk and likelihood of microbial proliferation (Low-, Medium-, and High Risk Compounded Sterile Products).  It is well established that even the best of conditions in a “sterile” pharmacy compounding process is highly prone to contamination , especially compared to GMP pharmaceutical manufacturing facilities.  It must be noted that this splitting of “sterility” into different categories of “sterile” is fundamentally different from the GMP pharmaceutical manufacturing approach of Quality by Design for sterile drug product which requires process validation and control yielding a sterile product stable for extended periods.

A second interesting argument has recently been put forward.  In a recent Wall Street Journal article, it was implied that a faulty “sterility test” was to blame for release of the tainted medication from NECC.  This position is inaccurate, as no sterility test available can actually test for product sterility (as was noted in the same WSJ article).  It is the robustness of the manufacturing process that serves as the Quality standard for sterile products.

The real problem is with the system of allowing the poor manufacturing and quality practices of pharmacies to produce large scale batches of medications that will not be used immediately, thus allowing microbial proliferation in the “sterile” container.  This point is also made by the recent ISMP Medication Safety Alert mentioned above.  Pharmacies have no GMP tradition, nor, at least seemingly in the current case in the news, at best a minimal concern about manufacturing cleanliness and contamination control.  They do (at least at the national level) seem very concerned about maintaining their prerogative “that compounding is a traditional right of pharmacists.”    FDA is clearly not to blame here, as consistent efforts to get this situation under control have been stymied by a Congress concerned about “excess government regulation” and the courts.

Pharmacies have no business operating as manufacturing facilities, and we have had plenty of warning before this crisis.  FDA reported in 2007 that the Agency had reports of 200 adverse events at that time involving 71 compounded products since 1990.   The general public has been made aware of some examples as well – a few of which are outlined below.  As you review these events, please also note that many involve shipment across state lines, and sometimes extremely large batch sizes.

2012

2011

2007

2005

  • Up to 25 patients in New Jersey and California contracted Serratia marcescens infections due to contaminated magnesium sulfate  prepared by Pharmedium, a compounding pharmacy located in Lake Forest, IL.
  • 6 cases of postsurgical endophthalmitis were reported due a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia.  This was recalled by the compounding pharmacy Custom-RX of Richfield, MN.
  • 10 patients died in Virgina after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods.  This product was made by Central Admixture Pharmacy Services, Inc. (CAPS), a subsidiary of B. Braun Medical located in Maryland (also see 1998 incident below).
  • Pseudomonas putida septicemia was reported in a special care nursery due to contaminated flush solutions prepared in a hospital pharmacy.
  • 36 cases of Pseudomonas fluorescens bloodstream infections were associated with a heparin/saline flush.  From the MMWR Report: “To produce its heparin/saline flush, IV Flush ordered heparin powder and sent it to a compounding pharmacy, where a concentrated heparin solution was made. This concentrated solution was then returned to IV Flush, where it was added to bags of saline solution, from which the syringes were filled.” IV Flush was located in Rowlett, Texas while the affected patients were in four states across the country.  A later research paper identified potentially 80 cases.

2004

2003

2002

2001

1999

1998

  • 11 children became septic in California and 10 tested positive for Enterobacter cloacae bloodstream infections associated with contaminated prefilled saline syringes from CAPS, Braun-McGaw of Detroit, MI.  (see also 2005 incident above).

1990

  • Four patients died of an Enterobacter  infection from a filter-sterilized cardioplegia solution (a parenteral with high potential for bacteremia) compounded in a Nebraska hospital.  In this episode five bottles of the solution tested were nonsterile, several subsequent bottles tested were sterile, and another 93 bottles were dispensed without being tested.
  •  2 patients lost their vision after becoming infected by Pseudomonas aeruginosa found in indomethacin eye drops compounded in a Pennsylvania drug store.

 


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